These studies are designed to provide preclinical information for the development of medications to be used in the treatment of drug abuse. The primary focus of this work is to determine pharmacological means for modulating behavioral and toxic actions of abused compounds, and to evaluate new chemical entities (synthesized in-house and from outside sources) for safety and efficacy in the design of potential rational treatment strategies. The primary findings and implications for the current year are: (1) Certain sigma-receptor ligands have shown an ability to antagonize some of the pharmacological effects of cocaine. Studies have indicated that these drugs are capable of blocking the locomotor stimulant effects of cocaine in rodents. In addition, several of the most highly specific sigma ligands are most effective in antagonizing this behavioral effect of cocaine. Further, the sensitivity that develops with repeated administration of cocaine is blocked by concurrent administration of one of several sigma ligands. The overdose toxicity that results from high dose cocaine treatment can be attenuated by treatment with these drugs. Ongoing studies will determine whether other behavioral effects of cocaine related to its abuse and toxicity can be similarly altered. In addition, these studies will address the mechanisms of these effects of sigma ligands and better document the nature of the interaction in order to determine if these drugs are suitable candidates for development as cocaine-abuse treatments. (2) A variety of compounds proposed by NIDA as potential treatments for cocaine abuse are being examined in preclinical screens for safety and efficacy as potential treatments for cocaine abuse. (3) The synthetic chemistry component of the laboratory is developing novel compounds as potential treatments against cocaine abuse.